Protein inhibitor or degrading agent, pharmaceutical composition containing same and pharmaceutical use

Abstract

A protein inhibitor or degrading agent, a pharmaceutical composition comprising same and a pharmaceutical use. Provided are a compound represented by general formula (I), and a pharmaceutical composition containing same. Also disclosed are an application of the compound of the general formula as a protein inhibitor and/or a protein degrading agent and a pharmaceutical use. PIN-Linker-E  (I)

1 . A compound of formula (I), or a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a racemate, a solvate, a hydrate, a polymorph, a prodrug or an isotopic variant thereof, and a mixture thereof,
   PIN-Linker-E  (I)
   wherein,   PIN represents:   
       
         
           
           
               
               
           
         
         wherein Q is C(R q1 ) 3 , C(O)R q1 , S(O)R q1 , SO 2 R q1 , P(O)R q1 R q2 , or NR q1 R q2 , and R q1  and R q2  are each independently selected from hydrogen, amino, —C 1-5  alkylene-R qn , —C 1-5  haloalkylene-R qn , —C 1-5  alkyleneoxy-R qn , —C 3-8  cycloalkylene-R qn , −3- to 8-membered heterocycloalkylene-R qn , —C(O)R qn , —S(O)R qn , SO 2 R qn , —C(O)NR 00 R qn , —NR 00 C(O)R qn , and —SO 2 NR 00 R qn ; 
         R qn  is selected from hydrogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         J 1  is N or CR J1 , J 2  is N or CR J2 , J 3  is N or CR J3 , and J 4  is N or CR J4 ; 
         V 1  is N or CR 1 , V 2  is N or CR 2 , V 3  is N or CR 3 , and V 4  is N or CR 4 ; 
         R 1 , R 2 , R 3 , R 4 , R J1 , R J2 , R J3 , and R J4  are each independently selected from hydrogen, hydroxy, cyano, acetyl, carboxy, nitro, halogen, amino, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         or, R 3  and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene; 
         or, R J2  and R J3 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene, or R J3  and R J4 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene; the substitution refers to that the 5- to 6-membered heteroaryl or benzene is optionally substituted with 1, 2, 3, or 4 substituents selected from hydrogen, halogen, amino, cyano, acetyl, C 1-5  alkyl, C 1-5  alkoxy, C 1-3  haloalkyl, C 3-8  cycloalkyl, and 3- to 8-membered heterocycloalkyl; 
         K 1  is N or CR k1 , K 2  is N or CR k2 , and K 4  is N or CR k4 , 
         R k1 , R k2 , and R k4  are identical or different, and are each independently selected from hydrogen, hydroxy, cyano, acetyl, —C(O)NR a R b , halogen, C 1-10  alkyl, C 1-5  alkylene-OC 1-5  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, —O—C 3-8  cycloalkyl, —O-3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         R k3  is not hydrogen, and R k3  represents —X 1 —Rx, 
         X 1  is selected from O, S, NR 00 , —C(O)—, —S(O)—, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)O—, —C(O)O—, —OC(O)—, —CH═CH—, —C≡C—, —(CR x1 R x2 ) x —, C 3-8  cycloalkylene, 3- to 8-membered heterocycloalkylene, C 6-10  arylene, and 5- to 14-membered heteroarylene; 
         Rx represents —(CR x3 R x4 ) x2 —R xn  or deuterium, R x1 , R x2 , R x3 , R x4 , and R xn  are each independently selected from hydrogen, cyano, hydroxy, acetyl, halogen, nitro, formyl, carboxy, amino, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; or, R x1  and R x2 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; 
         x and x2 are each independently 0, 1, 2, 3, 4, or 5, and x and x2 are not both 0; 
         or, R J3  and R k3  are connected to form a bond; 
         L 5  and L 6  are each independently selected from O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-10  alkylene, C 1-10  haloalkylene, C 1-10  alkyleneoxy, C 2-10  alkenylene, and C 2-10  alkynylene; 
         ring A is a saturated or unsaturated monocyclic alkylene, monocyclic heterocyclylene, polycyclic alkylene, or polycyclic heterocyclylene; 
         ring B is a saturated or unsaturated monocyclic alkylene, monocyclic heterocyclylene, polycyclic alkylene, or polycyclic heterocyclylene; 
         R is a bond, a saturated or unsaturated monocyclic alkylene, monocyclic heterocyclylene, polycyclic alkylene or polycyclic heterocyclylene, or a 7- to 11-membered mono-spiroheterocyclylene, 3- to 8-membered monocyclic heterocyclylene and 8- to 10-membered bicyclic heteroarylene substituted with 1, 2, or 3 R 0 s, wherein R 0  is selected from hydrogen, deuterium, halogen, ═O, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 3-8  cycloalkyl, and 3- to 8-membered heterocyclyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; the heteroatom of the mono-spiroheterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the bicyclic heteroarylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the monocyclic heterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the 3- to 8-membered heterocyclyl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; 
         Linker is absent, or represents: a C 1-20  alkylene chain, and any one or more methylene groups may optionally be substituted by one or more R L s, R L s are identical or different, and R L  is selected from O, S, NR 00 , —C(O)—, SO, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)—, —C(O)O—, —OC(O)O—, —CR 00 ═CR 00 —, —C≡C—, —(CH 2 ) r —, C 3-8  cycloalkylene, 3- to 8-membered heterocyclylene, C 6-10  arylene, and 5- to 14-membered heteroarylene; and any one methylene group may be substituted by 1 or 2 R L 's, and R L 's are identical or different and are hydrogen, halogen, amino, nitro, cyano, acetyl, C 1-10  alkyl, C 1-10  alkoxy, C 1-10  haloalkyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, or 5- to 14-membered heteroaryl, or two R's, together with the C atoms to which they are attached, form a C 3-8  cycloalkyl or 3- to 8-membered heterocyclyl; r is 1, 2, 3, 4, or 5; 
         E represents: 
       
       
         
           
           
               
               
           
         
         wherein G 1  is N or CR G1 , G 2  is N or CR G2 , G 3  is N or CR G3 , and G 4  is N or CR G4 ; 
         one of R G1 , R G2 , R G3 , and R G4  is attached to W, and the others are each independently selected from the group consisting of hydrogen, hydroxy, cyano, acetyl, acylamino, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         ring D is absent, such that L 7  is attached to a C atom or an N atom on the aromatic ring on which G 1  is located, or ring D is a substituted or unsubstituted C 6-10  aryl or a substituted or unsubstituted 5- to 14-membered heteroaryl; the substitution refers to that the C 6-10  aryl or 5- to 14-membered heteroaryl is optionally substituted, within their respective valence-permitted ranges, with 1, 2, or 3 substituents selected from hydrogen, halogen, C 1-10  alkyl, C 1-10  alkoxy, C 1-10  haloalkyl, C 1-10  haloalkoxy, C 2-10  alkenyl, C 2-10  alkynyl, cyano, nitro, acylamino, amino, and acetyl; 
         or, ring D is 
       
       
         
           
           
               
               
           
         
         G 5 , G 6 , and G 7  are each independently O, S, N, or C atom optionally substituted with 1 or 2 R G s, and R G  is hydrogen, hydroxy, amino, cyano, acetyl, carboxy, nitro, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, or 5- to 14-membered heteroaryl; or two R G s, together with the C atoms to which they are attached, form C═O, 3- to 8-membered cycloalkyl, or 3- to 8-membered heterocyclyl; 
         Z 3  and Z 4  are each independently selected from O, S, or NR 00 ; Z 5  is CR 00  or N; or the ring in which Z 5  is located is absent; 
         L 7  is a bond, O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-5  alkylene, C 1-5  haloalkylene, C 1-5  alkyleneoxy, C 2-6  alkenylene, or C 2-6  alkynylene; 
         W is a bond, O, S, NR 00 , —C(O)—, —S(O)—, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)O—, —C(O)O—, —OC(O)—, —CR 00 ═CR 00 —, —C≡C—, —(CR 23 R 24 ) r2 —, C 3-8  cycloalkylene, 3- to 8-membered heterocyclylene, C 6-10  arylene, and 5- to 14-membered heteroarylene; 
         R a , R b , R 00 , R 01 , R 02 , R 03 , R 04 , R 23 , and R 24  are each independently selected from hydrogen, cyano, acetyl, hydroxy, carboxy, nitro, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR c R d , C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         or R 01  and R 02 , or R 03  and R 04 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; or R 23  and R 24 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl; or R a  and R b , together with the N atom to which they are attached, form a 3- to 8-membered heterocyclyl; 
         r2 is 0, 1, 2, 3, or 4; 
         R c  and R d  are each independently hydrogen, C 1-5  alkyl, C 1-5  alkoxy, or C 1-5  haloalkyl; or R c  and Rd, together with the N atom to which they are attached, form a 3- to 8-membered heterocyclyl; 
         the above C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, or 5- to 14-membered heteroaryl, saturated or unsaturated monocycle, monocyclic heterocycle, polycycle and polycyclic heterocycle are unsubstituted or, within a valence-permitted range, each independently substituted by 1, 2, 3, 4, or more groups selected from the following B2 groups, and the B2 group is selected from hydrogen, ═O, cyano, acetyl, hydroxy, carboxy, nitro, halogen, C 1-5  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, NR e R f , 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, or 5- to 14-membered heteroaryl, wherein R e  and R f  are each independently hydrogen, C 1-5  alkyl, C 1-5  alkoxy, and C 1-5  haloalkyl; 
         provided that: 
         when PIN is formula (Ia) and Q is S(O) 2 -isopropyl, neither R k3  nor R k4  is methyl; 
         when PIN is formula (Ib), ring B is 
       
       
         
           
           
               
               
           
         
          Q is P(O)(CH 3 ) 2 , J 1 , J 2 , J 3 , J 4 , V 3  and K 1  are CH, and V 1  and V 2  are N, R 4  is not bromine, or neither R k3  nor R k4  is methyl. 
       
     
     
         2 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein, in the compound of formula (I),
 E represents   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R J1 , R J2 , R J3 , and R J4  are each independently selected from: hydrogen, hydroxy, cyano, acetyl, carboxy, nitro, halogen, amino, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 2-10  alkenyl, C 2-10  alkynyl, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         or, R 3  and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene; 
         or, R J2  and R J3 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene, or R J3  and R J4 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl or benzene, 
         the substitution refers to that the 5- to 6-membered heteroaryl or benzene is optionally substituted with 1, 2, 3, or 4 substituents selected from hydrogen, halogen, amino, cyano, acetyl, C 1-5  alkyl, C 1-5  alkoxy, C 1-3  haloalkyl, C 3-8  cycloalkyl, and 3- to 8-membered heterocycloalkyl; 
         x and x2 are each independently 0, 1, 2, 3, 4, or 5, and x and x2 are not both 0; 
         or, R J3  and R k3  are connected to form a bond; 
         Linker represents 
       
       
         
           
           
               
               
           
         
          wherein 
         L 1 , L 2 , L 3 , and L 4  each independently represents —R L1 —(CR 21 R 22 ) n3 —R L2 —(CR 31 R 32 ) n2 —; 
         R L1  and R L2  are each independently a bond, O, S, NR 00 , —C(O)—, SO, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)—, —C(O)O—, —OC(O)O—, —CH═CH—, —C≡C—, —(CR 41 R 42 ) r —, —(CR 41 R 42 ) r —O—, —O—(CR 41 R 42 ) r , C 3-8  cycloalkylene or 3- to 8-membered heterocycloalkylene, C 6-10  arylene, or 5- to 14-membered heteroarylene; 
         n2, n3, and r are each independently 0, 1, 2, 3, or 4; 
         R 21 , R 22 , R 31 , R 32 , R 41 , and R 42  are each independently selected from hydrogen, cyano, acetyl, hydroxy, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; or 
         R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; 
         L 5  and L 6  are each independently selected from O, S, NR 00 , C(O)NR 00 , NR 00 C(O), C 1-10  alkylene, C 1-10  haloalkylene, C 1-10  alkyleneoxy, C 2-10  alkenylene, and C 2-10  alkynylene; 
         W is a bond, O, S, NR 00 , —C(O)—, —S(O)—, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)O—, —C(O)O—, —OC(O)—, —CH═CH—, —C≡C—, —(CR 23 R 24 ) r2 —, C 3-8  cycloalkylene, 3- to 8-membered heterocycloalkylene, C 6-10  arylene, or 5- to 14-membered heteroarylene; 
         R 23  and R 24  are each independently selected from hydrogen, cyano, acetyl, hydroxy, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; or R 23  and R 24 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; r2 is 0, 1, 2, 3 or 4; 
         Z 1  is CH or N, and Z 2  is CR z1 R z2 , NR 00 , or C(O); 
         R z1  and R z2  are each independently selected from hydrogen, hydroxy, cyano, acetyl, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; or R z1  and R z2 , together with the C atoms to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; 
         G 1  is N or CR G1 , G 2  is N or CR G2 , G 3  is N or CR G3 , and G 4  is N or CR G4 ; 
         one of R G1 , R G2 , R G3 , and R G4  is attached to W, and the others are each independently selected from the group consisting of hydrogen, hydroxy, cyano, acetyl, halogen, amino, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; 
         R 00 , R a , and R b  are each independently hydrogen, cyano, acetyl, hydroxy, carboxy, nitro, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR c R d , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl or 5- to 14-membered heteroaryl; or R a  and R b , together with the N atom to which they are attached, form a 3- to 8-membered heterocycloalkyl; 
         R c  and R d  are each independently hydrogen, C 1-5  alkyl, C 1-5  alkoxy, or C 1-5  haloalkyl; or R c  and R d , together with the N atom to which they attached, form a 3- to 8-membered heterocycloalkyl; 
         the above C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, or 5- to 14-membered heteroaryl, saturated or unsaturated monocycle, monocyclic heterocycle, polycycle and polycyclic heterocycle are unsubstituted or, within a valence-permitted range, each independently substituted by 1, 2, 3, 4, or more groups selected from the following B2 groups, and the B2 group is selected from hydrogen, cyano, acetyl, hydroxy, carboxy, nitro, halogen, C 1-5  alkyl, C 1-5  alkoxy, C 1-5  alkylthio, NR e R f , 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl, wherein R e  and R f  are each independently hydrogen, C 1-5  alkyl, C 1-5  alkoxy, or C 1-5  haloalkyl; 
         provided that: 
         when PIN is formula (Ia) and Q is S(O) 2 -isopropyl, neither R k3  nor R k4  is methyl; 
         when PIN is formula (Ib) and ring B is pyrazine, neither R k3  nor R k4  is methyl. 
       
     
     
         3 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein, R k2  and R k4  are each independently selected from hydrogen, deuterium, halogen, cyano, acylamino, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 1-3  alkylene-OC 1-3  alkyl, C 3-6  cycloalkyl, and C 3-6  heterocycloalkyl; the C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 1-3  alkylene-OC 1-3  alkyl, C 3-6  cycloalkyl, and C 3-6  heterocycloalkyl are optionally substituted with 0, 1, 2, 3, or more substituents selected from deuterium, hydroxy, cyano, C 1-5  alkyl, C 1-5  haloalkyl, and C 1-5  alkoxy;
 or R k1  and R k2  are each independently hydrogen, F, Cl, Br, I, amino, hydroxy, cyano, acetyl, C 1-5  alkyl, C 1_5  haloalkyl, C 1-5  alkoxy, C 1-3  alkylene-OC 1-3  alkyl, C 3-6  cycloalkyl, or C 3-6  heterocycloalkyl; preferably, R k2  is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, or —O-oxetanyl; preferably R K4  is selected from hydrogen, deuterium, acylamino, cyano or C 1-5  alkyl, preferably methyl, ethyl, propyl, isopropyl, C 1-5  haloalkyl and C 1-5  alkoxy;   or, X 1  is selected from O, S, NR 00 , —C(O)—, —S(O)—, —SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)O—, —CH═CH—, —C≡C—, C 1-5  alkylene, C 3-6  cycloalkylene, 3- to 6-membered heterocycloalkylene, phenylene, 5- to 6-membered heteroarylene, and 8- to 10-membered bicyclic heteroarylene, wherein R 00  is selected from hydrogen and C 1-3  alkyl (preferably methyl, ethyl, or propyl; preferably hydrogen or methyl);   or, R k3  is selected from F, Cl, Br, I, hydroxy, cyano, formyl, nitro, carboxy, acetyl, —CO-amino, SOC 1-5  alkyl, SO 2 C 1-5  alkyl, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 1-5  alkylene-OC 1-5  alkyl, C 3-6  cycloalkyl, 3- to 6-membered heterocycloalkyl, —O—C 3-6  cycloalkyl, and —O-3- to 6-membered heterocycloalkyl; preferably, R k3  is hydroxy, cyano, formyl, nitro, carboxy, acetyl, —CO-amino, or —SO 2 -methyl; or R k3  is F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; or, R k3  is a C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-5  alkylene-OC 1-5  alkyl, C 3-6  cycloalkyl, 3- to 6-membered heterocycloalkyl, —O—C 3-6  cycloalkyl, or —O-3- to 6-membered heterocycloalkyl; the C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-5  alkylene, C 1-5  alkyl, C 3-6  cycloalkyl, or 3- to 6-membered heterocycloalkyl is optionally substituted with 0, 1, 2, 3, 4, 5, or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy;   or, R 4  is hydroxy, cyano, acetyl, carboxy, nitro, halogen, amino, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  alkenyl, C 2-6  alkynyl, NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, or 5- to 14-membered heteroaryl; the C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, and 5- to 14-membered heteroaryl are optionally substituted with 0, 1, 2, or 3 R 41 s; or, R 4  is halogen, C(O)NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, 7- to 11-membered spirocyclyl, or 8- to 12-membered spiroheterocyclyl;   the C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, 7- to 11-membered spirocyclyl, and 8- to 12-membered spiroheterocyclyl are optionally substituted with 0, 1, 2, or 3 R 41 s; preferably, R 4  is selected from fluorine, chlorine, bromine, amino, acylamino, acetyl, cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, trifluoromethyl, and C 1-6  alkyl; preferably, R 4  is hydrogen, —O—C 0-5  alkylene-C 3-8  cycloalkyl, or —OC 0-5  alkylene-3- to 8-membered heterocyclyl; preferably, R 4  is phenyl or 5- or 6-membered heteroaryl substituted with 0, 1, or 2 R 41 s; preferably, R 4  is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, phenyl, pyridinyl, pyrimidinyl, cyclopentyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, cyclohexyl, oxacyclohexyl, piperidinyl, piperazinyl, and morpholinyl substituted with 0, 1, or 2 R 41 s; R 41  is selected from hydrogen, deuterium, halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, OC 3-8  cycloalkyl, and —O-3- to 8-membered heterocyclyl (R 41  is preferably hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, or azacyclopentyl   
       
         
           
           
               
               
           
         
         or, ring A is a 3- to 8-membered monocyclic heterocyclylene, 7- to 16-membered spiroheterocyclylene, 7- to 14-membered fused heterocyclylene, 7- to 10-membered bridged heterocyclylene, phenylene, 5- or 6-membered monocyclic heteroarylene, or 8- to 10-membered bicyclic heteroarylene; preferably ring A is a 5- to 7-membered monocyclic heterocyclylene; 
         preferably, ring A is a 7- to 11-membered mono-spiroheterocyclylene; 
         or, the pharmaceutically acceptable salt is a hydrochloride, a formate, or a trifluoroacetate; 
         or, Linker represents 
       
       
         
           
           
               
               
           
         
          L 1 , L 2 , L 3  and L 4  each independently represent —R L1 —(CR 21 R 22 ) n3 —R L2 —(CR 31 R 32 ) n2 —; R L1  and R L2  are each independently a bond, O, NR 00 , —C(O)—, —CH═CH—, —C≡C—, —(CR 41 R 42 ) r —, or C 3-8  cycloalkylene; n2, n3, and r are each independently 0, 1, 2, 3, or 4; R 41  and R 42  are each independently selected from hydrogen, acetyl, halogen, C 1-5  alkyl, C 1-5  haloalkyl, or C 6-10  aryl; or, R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl; preferably, Linker represents 
       
       
         
           
           
               
               
           
         
          and L 1 , L 2 , L 3  and L 4  each independently represent —R L1 —(CR 21 R 22 ) n3 —R L2 —(CR 31 R 32 ) n2 —; R L1  is each independently a bond, O, NR 00 , —C(O)—, —(CR 41 R 42 ) r , or C 3-8  cycloalkylene; R L2  is each independently a bond, O, NR 00 , —C(O)—, —CH═CH—, —C≡C—, or C 3-8  cycloalkylene; n2, n3, and r are each independently 0, 1, 2, 3, or 4; R 41  and R 42  are each independently selected from hydrogen or C 1-5  alkyl; or, R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl; 
         or, R k2  is —CONH 2 ; 
         or, X 1  is —(CR x1 R x2 ) x —, R x1  and R x2  are each independently selected from hydrogen, C 1-5  alkyl (preferably C 1-3  alkyl, more preferably methyl, ethyl, propyl or isopropyl) and C 1-5  alkoxy, or R x1  and R x2 , together with the C atoms to which they are attached, form a C 3-6  cycloalkyl (preferably cyclopropyl or cyclobutyl) or 3- to 6-membered heterocycloalkyl (preferably oxetanyl); x is 0, 1, 2, 3, or 4; 
         or, Rx is hydrogen, cyano, hydroxy, acetyl, halogen, amino, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 2-10  alkenyl, C 2-10  alkynyl, C 3-6  cycloalkyl, 3- to 6-membered heterocycloalkyl, benzene, 5- to 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl. 
       
     
     
         4 - 6 . (canceled) 
     
     
         7 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein, R k3  represents —X 1 —Rx, and X 1  is selected from a C 3-8  cycloalkylene, 3- to 8-membered heterocycloalkylene, C 6-10  arylene, and 5- to 14-membered heteroarylene; Rx represents —(CR x3 R x4 ) x2 —R xn , and R x3 , R x4  and R xn  are each independently selected from hydrogen, cyano, hydroxy, acetyl, halogen, nitro, formyl, carboxy, amino, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 1-5  alkylthio, C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, and 5- to 14-membered heteroaryl; or R x1  and R x2 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; x2 is 0, 1, 2, 3, or 4;
 or, ring A represents: 
 
       
         
           
           
               
               
           
         
         wherein, Y 1  and Y 2  are each independently CH or N, Y 3  and Y 4  are each independently CH or N, t1, t2, t3 and t4 are each independently 0, 1, 2 or 3, and t5 and t6 are each independently 0, 1, 2 or 3, provided that: t1 and t3 are not both 0, and t2 and t4 are not both 0; 
         or, R is a bond, or R is a 3- to 8-membered monocyclic heterocyclylene, 7- to 16-membered spiro heterocyclylene, 7- to 10-membered bicyclic fused heterocyclylene, 7- to 10-membered bridged heterocyclylene, 5- or 6-membered heteroarylene, or 8- to 10-membered bicyclic heteroarylene; preferably, R is a bond; preferably, R is a 5- to 7-membered monocyclic heterocyclylene; preferably, R is a 7- to 11-membered mono-spiroheterocyclylene or 8- to 10-membered bicyclic heteroarylene; preferably, R is a 7- to 11-membered mono-spiroheterocyclylene or 8- to 10-membered bicyclic heteroarylene substituted with 0, 1, 2, or 3 R 0 s; R 0  is selected from hydrogen, deuterium, halogen, ═O, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 3-8  cycloalkyl, or 3- to 8-membered heterocyclyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl or heterocyclyl. 
       
     
     
         8 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 3 , wherein, X 1  is a 5- to 6-membered heteroarylene or 8- to 10-membered bicyclic heteroarylene, and Rx is H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ;
 or, ring A is selected from 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or, R represents: 
       
       
         
           
           
               
               
           
         
         wherein 
         ring C1 is a 5- to 6-membered heteroaryl or benzene, and ring C2 is a 5- to 6-membered saturated or unsaturated monocycle or a 5- to 6-membered saturated or unsaturated monoheterocycle, wherein the 5- to 6-membered heteroaryl, benzene, 5- to 6-membered saturated or unsaturated monocycle, or 5- to 6-membered saturated or unsaturated monoheterocycle is optionally substituted with 0, 1, 2, 3, or more substituents selected from hydrogen, D, halogen, amino, hydroxy, cyano, acetyl, C 1-5  alkyl, C 1-5  alkoxy, C 3-8  cycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; 
         preferably, ring C2 is a 5- to 7-membered azacycle; 
         Y 5  and Y 6  are each independently CH or N, Y 7  and Y 8  are each independently CH or N, s1, s2, s3 and s4 are each independently 0, 1, 2 or 3, and s5 and s6 are each independently 0, 1, 2 or 3, provided that: s1 and s3 are not both 0, and s2 and s4 are not both 0; or, R k3  is selected from 
       
       
         
           
           
               
               
           
         
         R a  and R b  are H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; 
         preferably, R k3  is a 5- or 6-membered heterocyclyl substituted with 0, 1, or 2 substituents selected from R b , and R b  is selected from hydrogen, deuterium, halogen, cyano, C 1-5  alkyl, C 1-5  haloalkyl, and C 1-5  alkoxy. 
       
     
     
         9 - 13 . (canceled) 
     
     
         14 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 8 , wherein, ring C1 is selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, benzene, pyridine, pyrimidine, pyrazine, or pyridazine; ring C2 is selected from cyclopentane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, cyclohexane, oxacyclohexane, piperidine, piperazine, morpholine, benzene, pyridine, pyrimidine, pyrazine, and pyridazine;
 or, R is selected from   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
          is connected with Linker while the other end is connected with ring A, or 
       
       
         
           
           
               
               
           
         
          is connected with ring A while the other end is connected with Linker; 
         or, L 1 , L 2 , L 3 , and L 4  are each independently selected from —R L1 -(CH 2 ) n5 —R L2 —(CH 2 ) n6 —, wherein R L1  and R L2  are each independently O, S, NR 00 , —C(O)—, —C(O)NR 00 —, —NR 00 C(O)—, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)NR 00 —, —NR 00 C(O)O—, —OC(O)—, —C(O)O—, —OC(O)O—, and (CH 2 ) r4 ; n5, n6, and r4 are each independently 0, 1, 2, 3, or 4, and R 00  is a C 1-3  alkyl (preferably methyl); 
         preferably, R L1  and R L2  are each independently selected from a bond, 5- or 6-membered heteroarylene, phenylene, C 3-8  cycloalkylene, C 3-8  heterocyclylene, CH 2 , CH 2 CH 2 , OCH 2 CH 2 , CH 2 CH 2 O, CH 2 CH 2 CH 2 , ethenylene, ethynylene, 
       
       
         
           
           
               
               
           
         
          wherein, the 5 or 6-membered heteroarylene, phenylene, C 3-8  cycloalkylene, C 3-8  heterocyclylene, and any methylene are optionally substituted, within their respective valence-permitted ranges, with 0, 1, 
         2, or 3 substituents selected from hydroxy, cyano, halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 2-6  alkenyl, C 2-6  alkynyl, NR a R b , acetyl, —C(O)NR a R b , C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, C 6-10  aryl, and 5- to 14-membered heteroaryl. 
       
     
     
         15 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, L 1  is (CR 21 R 22 ) n3 , wherein R 21  and R 22  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy or propoxy, and n3 is 0, 1, 2 or 3;
 preferably L 1  is (CR 21 R 22 ) n3 , wherein R 21  and R 22 , together with the C atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or oxetanyl, and n3 is 1 or 2;   preferably, L 1  is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), —C(O)O—, —OC(O)—, SO, SO 2 , SO 2 NR 00 , or NR 00 SO 2 ; R 00  is hydrogen or methyl;   preferably, L 1  is —CH═CH— or   preferably, L 1  is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2  (preferably CH 2  or CH 2 CH 2 );   preferably, L 1  is a bond;   preferably, L 1  is a C 3-6  cycloalkylene, 4- to 7-membered heterocyclylene, phenylene, or 5- or 6-membered heteroarylene (preferably cyclopropylene, cyclobutylene, cyclopentylene, azacyclopentylene, cyclohexylene, piperidylene, piperazinylene, 1,4-phenylene, 2,5-1H-pyrrolylene, 3,5-1H-pyrrolylene, 3,5-1H-pyrazolylene, 2,5-1H-triazolylene, or tetrazolylene);   or, L 2  is (CR 21 R 22 ) n3 , wherein R 21  and R 22  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy or propoxy, and n3 is 0, 1, 2 or 3; preferably L 2  is (CR 21 R 22 ) n3 , wherein R 21  and R 22 , together with the C atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or oxetanyl, and n3 is 1 or 2;   preferably, L 2  is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), —C(O)O—, —OC(O)—, SO, SO 2 , SO 2 NR 00 , or NR 00 SO 2 ; R 00  is hydrogen or methyl;   preferably, L 2  is —CH═CH— or   preferably, L 2  is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2  (preferably CH 2  or CH 2 CH 2 );   preferably, L 2  is a bond;   preferably, L 2  is a C 3-6  cycloalkylene, 4- to 7-membered heterocyclylene, phenylene, or 5- or 6-membered heteroarylene;   or, L 3  is (CR 21 R 22 ) n3 , wherein R 21  and R 22  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy or propoxy, and n3 is 0, 1, 2 or 3; preferably L 3  is (CR 21 R 22 ) n3 , wherein R 21  and R 22 , together with the C atom to which they   are attached, form cyclopropyl, cyclobutyl, cyclopentyl or oxetanyl, and n3 is 1 or 2;   preferably, L 3  is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), —C(O)O—, —OC(O)—, SO, SO 2 , SO 2 NR 00 , or NR 00 SO 2 ; R 00  is hydrogen or C 1-3  alkyl (preferably methyl, ethyl, or propyl);   preferably, L 3  is —CH═CH— or   preferably, L 3  is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2  (preferably CH 2  or CH 2 CH 2 );   preferably, L 3  is a bond;   preferably, L 3  is a C 3-6  cycloalkylene, 4- to 7-membered heterocyclylene, phenylene, or 5- or 6-membered heteroarylene;   or, L 4  is (CR 21 R 22 ) n3 , wherein R 21  and R 22  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, methoxy, ethoxy or propoxy, and n3 is 0, 1, 2 or 3; preferably L 4  is (CR 21 R 22 ) n3 , wherein R 21  and R 22 , together with the C atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl or oxetanyl, and n3 is 1 or 2;   preferably, L 4  is O, S, NR 00 , C(O), C(O)NR 00 , NR 00 C(O), —C(O)O—, —OC(O)—, SO, SO 2 , SO 2 NR 00 , or NR 00 SO 2 ; R 00  is hydrogen or methyl;   preferably, L 4  is —CH═CH— or   preferably, L 4  is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2  (preferably CH 2  or CH 2 CH 2 );   preferably, L4 is a bond;   preferably, L 4  is a C 3-6  cycloalkylene, 4- to 7-membered heterocyclylene, phenylene, or 5- or 6-membered heteroarylene;   or, W is a bond, O, S, NR 00 , —C(O)—, —S(O)—, SO 2 , —C(O)NR 00 —, —NR 00 C(O)—, —NR 00 C(O) NR 00 —, —SO 2 NR 00 —, —NR 00 SO 2 —, —NR 00 C(O)O—, —C(O)O—, —OC(O)—, —OC(O)O—, —CH═CH—, —C≡C—, —(CR 43 R 44 ) n8 —, C 3-6  cycloalkylene, 3- to 6-membered heterocycloalkylene, phenylene, 5- to 6-membered heteroarylene, or 8- to 10-membered arylene or heteroarylene, wherein R 00 , R 43 , and R 44  are each independently hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopentyl, or cyclohexyl, or R 43  and R 44 , together with the C atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl, and n8 is 0, 1, 2, or 3;   preferably, W is 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, piperazinylene, or pyridinylene;   preferably, W is CH 2 , O, S, —N(methyl)-, —CH═CH—, or C≡C; preferably, W is CH 2 ; preferably, W is O or S; preferably, W is —CH═CH— or C≡C;   or, ring B is selected from a 3- to 8-membered saturated or unsaturated cycloalkyl, 3- to 8-membered saturated or unsaturated heterocycloalkyl, 6- to 10-membered aryl, and 5- to 14-membered heteroaryl; preferably, ring B is a 5- to 7-membered saturated monocyclic heterocyclyl, benzene, or 5- to 6-membered heteroaryl; preferably, ring B is benzene or 5- to 6-membered heteroaryl; preferably, ring B is a 5- to 7-membered saturated monoheterocyclyl;   preferably, ring B is cyclopentane, tetrahydropyrrole, 1,3-dioxolane, oxolane, 1,4-dioxane, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, pyrrole, imidazole, pyrazole, piperidine, piperazine, benzene, pyridine, pyridazine, or pyrimidine; preferably, ring B is 1,3-dioxolane, oxolane, 1,4-dioxane, imidazole, benzene, or pyrimidine; preferably, ring B is a 5- to 6-membered heteroaryl; preferably, ring B is 1,4-dioxane or 1,3-dioxolane.   
     
     
         16 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, 
       
         
           
           
               
               
           
         
         “ ” represents a connection site; 
         R C  is hydrogen, F, Cl, Br, I, hydroxy, cyano, formyl, nitro, carboxy, acetyl, SOC 1-5  alkyl, SO 2 C 1-5  alkyl, C 1-5  alkyl, C 1-5  haloalkyl, C 1-5  alkoxy, C 1-5  alkyl-OC 1-5  alkyl, C 3-6  cycloalkyl, 3- to 6-membered heterocycloalkyl, —O—C 3-6  cycloalkyl, or —O-3- to 6-membered heterocycloalkyl; r3 is 0, 1, 2, or 3; 
         or, V 1  and V 2  are both N, V 3  is CR 3 , and V 4  is CR 4 , wherein R 3  is hydrogen, and R 4  is hydrogen, halogen, amino, cyano, acetyl, C 1-3  alkyl, C 1-3  alkoxy, or C 1-3  haloalkyl (preferably fluorine or chlorine); 
         preferably, V 1  and V 2  are both N, V 3  is CR 3 , and V 4  is CR 4 , wherein R 3  and R 4 , together with the atoms to which they are attached, form a substituted or unsubstituted 5- to 6-membered heteroaryl; the substitution refers to that the 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, halogen, amino, cyano, acetyl, C 1-3  alkyl, C 1-3  alkoxy, and C 1-3  haloalkyl; 
         preferably, R 3  and R 4 , together with the atoms to which they are attached, form 1H-pyrrole, 1H-pyrazole, or 1H-imidazole; 
         or, L 5  and L 6  are each independently selected from a bond, NH, CONH, NHCO, C 1-3  alkylene (preferably methylene or ethylene), C 2-6  alkenylene, and C 2-6  alkynylene; 
         or, E is selected from 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         one of R G1 , R G2 , R G3 , and R G4  is attached to W, the others are each independently selected from hydrogen, hydroxy, cyano, acetyl, fluorine, chlorine, bromine, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, and —CHFCHF 2 ; preferably, R G1 , R G2 , R G3 , and R G4  are each independently hydrogen, halogen (preferably F), C 1-3  alkyl, or C 1-3  haloalkyl; 
         preferably, R G1 , R G2 , R G3 , R G4 , and Ro are each independently hydrogen, deuterium, cyano, halogen (preferably F), C 1-3  alkyl, or C 1-3  haloalkyl (preferably methyl or trifluoromethyl); 
         or, J 1  is N, J 2  is CR J2 , J 3  is CR J3 , and J 4  is CR J4 ; or J 1  is CR J1 , J 2  is N, J 3  is CR J3 , and J 4  is CR J4 ; or 
         J 1  is CR J1 , J 2  is CR J2 , J 3  is N, and J 4  is CR J4 ; or J 1  is CR J1 , J 2  is CR J2 , J 3  is CR J3 , and J 4  is N; or J 1  is N, J 2  is N, J 3  is CR J3 , and J 4  is CR J4 ; or J 1  is N, J 2  is CR J2 , J 3  is N, and J 4  is CR J4 ; or J 1  is N, J 2  is CR J2 , J 3  is CR J3 , and J 4  is N; or J 1  is CR J1 , J 2  is N, J 3  is N, and J 4  is CR J4 ; or J 1  is CR J1 , J 2  is N, J 3  is CR J3 , and J 4  is N; or J 1  is CR J1 , J 2  is CR J2 , J 3  is N, and J 4  is N. 
       
     
     
         17 . (canceled) 
     
     
         18 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, R J1 , R J2 , R J3 , and R J4  are each independently selected from H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, and —CHFCHF 2 ;
 preferably, R J3  and R J4  are hydrogen, and R J1  and R J2  are each independently selected from F, Cl, Br, I, methyl, ethyl, propyl, cyclopropyl, or a substituted or unsubstituted benzene or 5- to 6-membered heteroaryl; the substitution refers to that the benzene or 5- to 6-membered heteroaryl is optionally substituted with 1, 2, or 3 substituents selected from hydrogen, halogen, amino, cyano, acetyl, C 1-3  alkyl, C 1-3  alkoxy, and C 1-3  haloalkyl; 
 preferably, R J1 , R J3 , and R J4  are hydrogen, and R J2  is selected from H, F, Cl, Br, methyl, ethyl, 3- to 8-membered cycloalkyl, benzene, or 5- to 6-membered heteroaryl; or R J1 , R J2 , R J3 , and R J4  are hydrogen; preferably, R J1 , R J3 , and R J4  are hydrogen, and R J2  is methyl, ethyl, cyclopropyl, benzene, or 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 1-ethyl-1H-pyrazol-4-yl, 1-ethyl-1H-imidazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl or 1-isopropyl-1H-imidazol-4-yl; 
 or, Q is C(R q1 ) 3 , C(O)R q1 , S(O)R q1 , SO 2 R q1 , P(O)R q1 R q2 , or NR q1 R q2 , wherein R q1  and R q2  are each independently selected from methyl, ethyl, propyl, isopropyl, amino, acetyl, methylsulfonyl, acylamino, and aminoacyl, and R q1  and R q2  are preferably C 1-6  alkyl or C 1-6  alkoxy. 
 
     
     
         19 . The compound of formula (I), or the pharmaceutically acceptable salt,
 the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein,   PIN represents:   
       
         
           
           
               
               
           
         
         R 3  and R 4 , together with the atoms to which they are attached, form 1H-pyrrole, wherein “ ” is a single bond or absent; r5 is 0, 1, 2, 3, 4, or 5; 
         U, T, and M are each independently C, N, O, or S, and U, T, and M are each independently substituted, within a valence-permitted range, with 1 or 2 R 0 s, wherein R 0  is selected from hydrogen, hydroxy, halogen, cyano, acetyl, C 1-5  alkyl (preferably C 1-3  alkyl), C 1-5  alkoxy (preferably C 1-3  alkoxy), C 1-5  haloalkyl (preferably C 1-3  haloalkyl), C 3-6  cycloalkyl, or 3- to 6-membered heterocycloalkyl; m 2  is 0, 1, or 2; preferably R 0  is hydrogen or halogen (preferably fluorine or chlorine); 
         or, E represents (II-i-1): 
       
       
         
           
           
               
               
           
         
         wherein L 7  is a bond or NH, and Z 5  is N or CH; 
         R 05  is hydrogen, halogen, cyano, acetyl, acylamino, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, or C 1-3  haloalkoxy; 
         ring D is absent, L 7  is attached to a benzene ring, or ring D is selected from benzene, pyridine, pyrimidine, pyrazine, pyridazine, cyclohexane, oxocyclohexane, cyclopentane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, or triazole; and ring D is substituted, within a valence-permitted range, with 1, 2, or 3 substituents selected from hydrogen, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 3-6  cycloalkyl, C 3-6  heterocycloalkyl, or halogen. 
       
     
     
         20 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, the compound of formula (I) is any one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein 
         preferably, hydrogen of the compound of formula (I) may optionally be substituted by 1, 2, 3, 4, 5, or more deuterium. 
       
     
     
         21 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, the compound of formula (I) is the compound of formula (III-1-1) or (III-1-2): 
       
         
           
           
               
               
           
         
         wherein 
         R 4  is halogen (preferably chlorine or bromine); R k2  is hydrogen or C 1-5  alkoxy (preferably C 1-3  alkoxy, more preferably methoxy); 
         R k3  is halogen, acetyl, cyano, C 1-5  alkyl, C 3-6  cycloalkyl, C 1-5  haloalkyl, or C 1-5  alkoxy; 
         L 1  is a bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, NH, CONH, NHCO, —N(methyl)-, O, C(O)O, OC(O), or (CR 21 R 22 )n 3 , wherein R 21  and R 22  are each independently hydrogen or methyl, or R 21  and R 22 , together with the C atom to which they are attached, form a C 3-6  cycloalkyl or 3- to 6-membered heterocycloalkyl, and n 3  is 0, 1, 2, or 3; 
         L 2  is a bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n 3 , wherein R 21  and R 22  are each independently hydrogen or methyl, or R 21  and R 22 , together with the C atom to which they are attached, form a C 3-6  cycloalkyl or 3- to 6-membered heterocycloalkyl, and n 3  is 0, 1, 2, or 3; 
         L 3  is a bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n 3 , wherein R 21  and R 22  are each independently hydrogen or methyl, or R 21  and R 22 , together with the C atom to which they are attached, form a C 3-6  cycloalkyl or 3- to 6-membered heterocycloalkyl, and n 3  is 0, 1, 2, or 3; 
         L 4  is a bond, CH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CO, NH, CONH, NHCO, O, C(O)O, OC(O), or (CR 21 R 22 )n 3 , wherein R 21  and R 22  are each independently hydrogen or methyl, or R 21  and R 22 , together with the C atom to which they are attached, form a C 3-6  cycloalkyl or 3- to 6-membered heterocycloalkyl, and n 3  is 0, 1, 2, or 3; Z 1  is CH or N, and Z 2  is CH 2  or C(O); W is CH 2 , O, S, alkenylene, or C≡C; R 0  is H, D, halogen, hydroxy, cyano, C 1-3  alkyl, or C 1-3  alkoxy; 
         preferably, 
         R 4  is chlorine or bromine (preferably chlorine); R k2  is hydrogen or methoxy; R k3  is selected from fluorine, chlorine, bromine, acetyl, methyl, ethyl, isopropyl, propyl, cyclopropyl, —O-oxetanyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, and —CHFCHF 2 ; 
         L 1 , L 2 , L 3 , and L 4  are each independently a bond, CH 2 , or CH 2 CH 2  (preferably, L 1 , L 2 , L 3 , and L 4  are each independently CH 2 , more preferably, L 1  and L 2  are each a bond or CH 2 , and L 3  and L 4  are CH 2 ); Z 1  is CH or N, Z 2  is CH 2  or C(O); W is CH 2 , O, S, or C≡C (preferably CH 2  or C≡C, more preferably C≡C); R 0  is H, D, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, or isopropyl (preferably hydrogen, more preferably F, even more preferably C 1-3  alkyl or C 1-3  haloalkyl). 
       
     
     
         22 . (canceled) 
     
     
         23 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 2 , wherein, the compound of formula (I) is the compound of formula (III-2-1) or (III-2-5): 
       
         
           
           
               
               
           
         
          wherein 
         Q is P(O)(C 1-3  alkyl) 2  or N(C 1-3  alkyl)methylsulfonyl; 
         Y 1  is CH or N, Y 2  is CH or N, and t1, t2, t3 and t4 are each independently 1 or 2; ring A is a 5- to 7-membered heterocyclylene or 3- to 8-membered cycloalkylene; R 0  is selected from hydrogen, deuterium, cyano, F, C 1-6  alkyl, or C 1-6  alkoxy; 
         or, the compound of formula (I) is the compound of formula (III-2-2) or (III-2-3): 
       
       
         
           
           
               
               
           
         
         wherein R 4  is chlorine or bromine; Y 1  is N, Y 2  is CH, and t1, t2, t3 and t4 are each independently 1 or 2; R k2  is hydrogen, methoxy, ethoxy, or O-oxetanyl; R k3  is selected from fluorine, chlorine, bromine, cyano, acetyl, methyl, ethyl, isopropyl, propyl, cyclopropyl, —O-oxetanyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; 
         L 1 , L 2 , L 3 , and L 4  are each independently a bond, CH 2 , or CH 2 CH 2  (preferably, L 1 , L 2 , L 3 , and L 4  are each independently CH 2 , more preferably, L 1  and L 2  are each a bond or CH 2 , and L 3  and L 4  are CH 2 , even more preferably, L 1 , L 2 , L 3 , and L 4  are each independently a bond); 
         W is CH 2 , O, or S (preferably O); Z 1  is CH or N, and Z 2  is CH 2  or C(O); R 0  is selected from hydrogen, fluorine, chlorine, and methyl; 
         or, the compound of formula (I) is the compound of formula (Ib-1) or (Ib-2): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 0  is H, D, fluorine, chlorine, bromine, hydroxy, cyano, methyl, ethyl, propyl, or isopropyl (preferably hydrogen, more preferably F, even more preferably C 1-3  alkyl or C 1-3  haloalkyl); 
         U, T, and M are each independently C, N, O, or S, and U, T, and M are each independently substituted, within a valence-permitted range, with 1 or 2 R 0 s, wherein R 0  is selected from hydrogen, hydroxy, halogen, cyano, acetyl, C 1-5  alkyl (preferably C 1-3  alkyl), C 1-5  alkoxy (preferably C 1-3  alkoxy), C 1-5  haloalkyl (preferably C 1-3  haloalkyl), C 3-6  cycloalkyl, or 3- to 6-membered heterocycloalkyl; m 2  is 0, 1, or 2; preferably R 0  is hydrogen or halogen (preferably fluorine or chlorine); 
         preferably, T is O, S, or C; preferably, T is O or N; M is O, S, or C, and preferably M is O or N; 
         U is C or N. 
       
     
     
         24 - 27 . (canceled) 
     
     
         28 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein the compound is selected from Table 1. 
     
     
         29 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein, E is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 05  is hydrogen, fluorine, cyano, acetyl, acylamino, fluoromethyl, difluoromethyl, or trifluoromethyl; preferably R 05  is hydrogen, deuterium, C 1-6  alkyl, C 1-6  alkoxy, cyano, or C 1-6  haloalkyl; R 00  is hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopropyl; W is CH 2 , O, S, NH, —N(methyl)-, or —C≡C; 
         or, R k3  is selected from 
       
       
         
           
           
               
               
           
         
          halogen, cyano, acetyl, C 1-5  alkyl, C 1-5  alkylene-OC 1-5  alkyl, and C 3-6  cycloalkyl, wherein the C 1-5  alkyl is optionally substituted with 0, 1, 2, 3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, cyano, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy; R a  and R b  are H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; preferably, R k3  is selected from 
       
       
         
           
           
               
               
           
         
          F, Cl, Br, I, cyano, acetyl, ethyl, C 1-5  alkylene-OC 1-5  alkyl, and C 3-6  cycloalkyl, wherein the C 1-5  alkyl is optionally substituted with 0, 1, 2, 3, 4, or 5 substituents selected from deuterium, hydroxy, cyano, C 1-3  alkyl, and C 1-3  alkoxy; R a  is H, methyl, ethyl, propyl, or isopropyl; R b  is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; more preferably, R k3  is selected from 
       
       
         
           
           
               
               
           
         
          F, Cl, Br, I, cyano, acetyl, ethyl, C 1-5  alkylene-OC 1-5  alkyl, and C 3-6  cycloalkyl, wherein the C 1-5  alkyl is optionally substituted with 0, 1, 2, or 3 substituents selected from deuterium, hydroxy, cyano, C 1-3  alkyl, and C 1-3  alkoxy; R a  is H, methyl, ethyl, propyl, or isopropyl; R b  is H, methyl, ethyl, propyl, or isopropyl; 
         or, R 4  is hydrogen, hydroxy, cyano, C(O)NR a R b , halogen, C 1-10  alkyl substituted with 0, 1 or 2 R 41 s, or 5- to 6-membered heteroaryl substituted with 0, 1 or 2 R 41 s; the heteroatom of the 5- to 6-membered heteroaryl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; or, R 3  and R 4 , together with the atoms to which they are attached, form a 5- to 6-membered heteroaryl or benzene substituted with 0, 1 or 2 R 41 s; the heteroatom of the 5- to 6-membered heteroaryl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; R a  and R b  are each independently hydrogen, cyano, acetyl, hydroxy, carboxy, nitro, halogen, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 1-10  alkylthio, NR c R d , C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, or 5- to 14-membered heteroaryl; or R a  and R b , together with the N atom to which they are attached, form a 3- to 8-membered heterocycloalkyl; the heteroatom of the 5- to 14-membered heteroaryl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatom is 1, 2, or 3; the heteroatom of the 3- to 8-membered heterocycloalkyl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; 
         R 41  is selected from hydrogen, deuterium, halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 3-8  cycloalkyl, 3- to 8-membered heterocyclyl, OC 3-8  cycloalkyl, and —O-3- to 8-membered heterocyclyl; the heteroatom of the 3- to 8-membered heterocycloalkyl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; 
         preferably, R 4  is hydrogen, hydroxy, cyano, C(O)NR a R b , halogen, C 1-10  alkyl substituted with 0, 1 or 2 R 41 s, or 5- to 6-membered heteroaryl substituted with 0, 1 or 2 R 41 s; the heteroatom of the 5- to 6-membered heteroaryl is nitrogen and/or oxygen, and the number of the heteroatom is 1, 2, or 3; or R 3  and R 4 , together with the atoms to which they are attached, form a 5- to 6-membered heteroaryl or benzene substituted with 0, 1, or 2 R 41 s; the heteroatom of the 5- to 6-membered heteroaryl is nitrogen and/or oxygen, and the number of the heteroatom is 1, 2, or 3; R a  and R b  are each independently hydrogen or C 1-5  alkyl; R 41  is selected from hydrogen, deuterium, halogen, C 1-5  alkyl, C 1-5  haloalkyl, and C 1-5  alkoxy; more preferably, R 4  is hydrogen, halogen, or 5- to 6-membered heteroaryl; the heteroatom of the 5- to 6-membered heteroaryl is nitrogen, and the number of heteroatom is 1, 2, or 3; or, R 3  and R 4 , together with the atoms to which they are attached, form a 5- to 6-membered heteroaryl or benzene; the heteroatom of the 5- to 6-membered heteroaryl is nitrogen, and the number of heteroatom is 1, 2, or 3; R a  and R b  are each independently hydrogen or C 1-10  alkyl; 
         or, ring A is a 3- to 8-membered monocyclic heterocyclylene or 7- to 16-membered spiroheterocyclylene; the heteroatom of the monocyclic heterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the spiroheterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatoms is 1, 2, or 3; preferably, ring A is a 3- to 6-membered monocyclic heterocyclylene or 7- to 11-membered spiroheterocyclylene; the heteroatom of the monocyclic heterocyclylene is nitrogen, oxygen, or sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the spiroheterocyclylene is nitrogen, oxygen, or sulfur, and the number of the heteroatom is 1, 2, or 3; more preferably, ring A is a 3- to 8-membered monocyclic heterocyclylene or 7- to 11-membered spiroheterocyclylene; the heteroatom of the monocyclic heterocyclylene is N, and the number of heteroatom is 1 or 2; the heteroatom of the spiroheterocyclylene is N, and the number of heteroatom is 1 or 2; 
         or, R is a bond, or 7- to 11-membered mono-spiroheterocyclylene, 3- to 8-membered monocyclic heterocyclylene, and 8- to 10-membered bicyclic heteroarylene substituted with 0, 1, 2, or 3 R 0 s, wherein R 0  is selected from hydrogen, deuterium, halogen, ═O, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 3-8  cycloalkyl, and 3- to 8-membered heterocyclyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; the heteroatom of the mono-spiroheterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the bicyclic heteroarylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; 
         the heteroatom of the monocyclic heterocyclylene is selected from one or more of nitrogen, 
         oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the 3- to 8-membered heterocyclyl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; preferably, R is a bond, or 7- to 11-membered mono-spiroheterocyclylene, 3- to 8-membered monocyclic heterocyclylene, and 8- to 10-membered bicyclic heteroarylene substituted with 0, 1, 2, or 3 R 0 s; R 0  is selected from hydrogen, ═O and C 1-6  alkyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; the heteroatom of the bicyclic heteroarylene is nitrogen, oxygen, or sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the spiroheterocyclylene is nitrogen, oxygen, or sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the monocyclic heterocyclylene is nitrogen, oxygen, or sulfur, and the number of the heteroatom is 1, 2, or 3; more preferably, R is a bond, or 7- to 11-membered mono-spiroheterocyclylene, 5- or 6-membered monocyclic heterocyclylene, and 8- to 10-membered bicyclic heteroarylene substituted with 0, 1, 2, or 3 R 0 s; R 0  is selected from hydrogen, ═O, and C 1-6  alkyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; the heteroatom of the mono-spiroheterocyclylene is N, and the number of the heteroatom is 1 or 2; 
         the heteroatom of the bicyclic heteroarylene is N, and the number of the heteroatom is 1 or 2; the heteroatom of the 6-membered monocyclic heterocyclylene is N, and the number of the heteroatom is 1 or 2; 
         or, Linker represents: 
       
       
         
           
           
               
               
           
         
          wherein R L1  and R L3  are each independently O, S, CO, SO, SO 2 , N(R 00 ), or (CR 21 R 22 ) r ; R 21  and R 22  are hydrogen, acetyl, halogen, amino, C 1-10  alkyl, C 1-10  haloalkyl, C 1-10  alkoxy, C 2-10  alkenyl, C 2-10  alkynyl, C 3-8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10  aryl, or 5- to 14-membered heteroaryl; or 
         R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl or 3- to 8-membered heterocycloalkyl; R L2 s are identical or different and R L2  is O, S, CO, N(R 00 ), C(O)O, OC(O), C(O)NH, NHC(O) or NHC(O)NH, phenylene, alkynylene, cyclopropylene, 1,4-piperazinylene, or triazolylene; R 00  is hydrogen or C 1-10  alkyl, and n2 and n4 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; r, n0, and n3 are 0, 1, 2, 3, or 4; 
         preferably, Linker represents: 
       
       
         
           
           
               
               
           
         
          wherein R L1  and R L3  are each independently O, CO, N(R 00 ), or (CR 21 R 22 ) r , and R 21  and R 22  are hydrogen, acetyl, C 1-5  alkyl, C 6-10  aryl, or C 1-5  haloalkyl; or, R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl; R L2 s are identical or different, and R L2  is O, CO, N(R 00 ), alkynylene 
       
       
         
           
           
               
               
           
         
          or cyclopropylene; R 00  is hydrogen or C 1-5  alkyl, and n2 and n4 are each independently 0, 1, 2, or 3; r, n0, and n3 are 0, 1, 2, 3, or 4; more preferably, Linker represents: 
       
       
         
           
           
               
               
           
         
          wherein R L1  and R L3  are each independently O, N(R 00 ), or (CR 21 R 22 ) r , and R 21  and R 22  are hydrogen or C 1-5  alkyl; or, R 21  and R 22 , together with the C atom to which they are attached, form a 3- to 8-membered cycloalkyl; R L2 s are identical or different, and R L2  is O, CO, N(R 00 ), alkynylene 
       
       
         
           
           
               
               
           
         
          alkenylene 
       
       
         
           
           
               
               
           
         
          or cyclopropylene 
       
       
         
           
           
               
               
           
         
          R 00  is hydrogen or C 1-5  alkyl, and n2 and n4 are each independently 0, 1, 2, or 3; r, n0, and n3 are 0, 1, 2, 3, or 4; even more preferably, Linker represents: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or, R J1 , R J3 , and R J4  are hydrogen; 
         or, R J2  is selected from hydrogen, F, Cl, Br, and C 1-5  alkyl; 
         or, R J3  and R J4  are hydrogen; 
         or, R J1  and R J2  are each independently selected from hydrogen, F, Cl, Br, and C 1-5  alkyl; 
         or, V 3  is N or CR 3 , R 3  is hydrogen, or R 3  and R 4 , together with the atoms to which they are attached, form a 5- to 6-membered heteroaryl or benzene substituted with 0, 1, or 2 R 41 s; the heteroatom of the 5- to 6-membered heteroaryl is nitrogen, and the number of the heteroatom is 1, 2, or 3; V 3  is N or CR 3 ; 
         or, W is O or —C≡C—; 
         or, Q is P(O)R q1 R q2 , wherein R q1  and R q2  are each independently C 1-6  alkyl or C 1-6  alkoxy; 
         or, V 4  is N or CR 4 , wherein R 4  is hydrogen, hydroxy, cyano, C(O)NR a R b , halogen, C 1-10  alkyl substituted with 0, 1, or 2 R 41 s, or 5- to 6-membered heteroaryl substituted with 0, 1, or 2 R 41 s; 
         the heteroatom of the 5- to 6-membered heteroaryl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; 
         or, R k3  is selected from 
       
       
         
           
           
               
               
           
         
          halogen, cyano, acetyl, C 1-5  alkyl, C 1-5  alkylene-OC 1-5  alkyl, or C 3-6  cycloalkyl, wherein the C 1-5  alkyl is optionally substituted with 0, 1, 2, 3, 4, or 5 substituents selected from deuterium, halogen, hydroxy, cyano, 
         C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy; R a  and R b  are H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, fluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CH 2 F, —CHFCH 3 , —CH 2 CHF 2 , —CF 2 CH 3 , —CHFCH 2 F, —CH 2 CF 3 , —CF 2 CH 2 F, or —CHFCHF 2 ; 
         or, R is a bond, or a 7- to 11-membered mono-spiroheterocyclylene, 3- to 8-membered monocyclic heterocyclylene, and 8- to 10-membered bicyclic heteroarylene substituted with 0, 1, 2, or 3 R 0 s, wherein R 0  is selected from hydrogen, deuterium, halogen, ═O, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 3-8  cycloalkyl, and 3- to 8-membered heterocyclyl, or two R 0 s, together with the C atom to which they are attached, form a 3- to 6-membered cycloalkyl; the heteroatom of the mono-spiroheterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the bicyclic heteroarylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the monocyclic heterocyclylene is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3; the heteroatom of the 3- to 8-membered heterocyclyl is selected from one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatom is 1, 2, or 3. 
       
     
     
         30 - 31 . (canceled) 
     
     
         32 . A compound, wherein the compound is represented by formula (1c-1), (1e-1), (1c-1-1), (1e-1-1), (1c-1-2), or (1e-1-2): 
       
         
           
           
               
               
           
         
         wherein, 
         in formula (1c-1), when R is a bond, NH is NH on ring A; when R is not a bond, NH is NH on ring R; 
         Sub is selected from OH, SH, C(O)OH, S(O)OH, S(O) 2 OH, NH, or a leaving group selected from fluorine, chlorine, bromine, iodine, boronic acid, boronate, —OMs or —OTF; 
         the variables in the formula are defined in  claim 1 ; or, the compound is any one of the compounds in Table 2 or a salt thereof. 
       
     
     
         33 . A pharmaceutical composition, comprising the compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , and a pharmaceutically acceptable excipient, wherein preferably, the pharmaceutical composition further comprises an additional therapeutic agent. 
     
     
         34 . A method for inhibiting EGFR, ROS1, or ALK, comprising administering the compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1  to a subject. 
     
     
         35 . A method for treating cancer, comprising administering the compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1  to a subject;
 preferably, the cancer is selected from lung cancer; lymphoma; inflammatory myofibroblastoma; colorectal cancer; cerebral glioma; astroblastoma; ovarian cancer; bone marrow cancer; transplantation-related cancer; neutropenia; leukemia; Wagner-Unverricht syndrome; bronchial carcinoma; prostate cancer; breast cancer; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; sarcoma; a tumor resistant to targeted therapies; or a tumor or disease dependent on ALK, ROS1 or EGFR, or any mutein thereof; 
 more preferably, the cancer is selected from small cell lung cancer; non-small cell lung cancer; diffuse large B-cell lymphoma; non-Hodgkin's lymphoma; anaplastic lymphoma; anaplastic large cell lymphoma; CD20-positive lymphoma; primary lymphoma; B cell lymphoma; recurrent B-cell non-Hodgkin's lymphoma; recurrent diffuse large B-cell lymphoma; recurrent mediastinal (thymic) large B-cell lymphoma; primary mediastinal (thymic) large B-cell lymphoma; recurrent transformed non-Hodgkin's lymphoma; refractory B-cell non-Hodgkin's lymphoma; refractory diffuse large B-cell lymphoma; refractory primary mediastinal (thymic) large B-cell lymphoma; refractory transformed non-Hodgkin's lymphoma; multiple myeloma; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; plasma cell myeloma; smoldering myeloma; smoldering multiple myeloma; myelofibrosis; acute myeloid leukemia (AML); leukemia-associated anemia; chronic granulocytic leukemia; B cell chronic lymphocytic leukemia; Wagner-Unverricht syndrome; bronchial carcinoma; prostate cancer; triple-negative breast cancer; sporadic breast cancer; a patient with Cowden disease; thyroid cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; large intestine adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; melanoma; brain cancer; oral cancer; rhabdomyosarcoma; various adipose-derived tumors; Ewing sarcoma/primitive neuroectodermal tumor (Ewing/PNET); leiomyosarcoma; a tumor resistant to EGFR-, ROS1- or ALK-targeted therapies, anaplastic lymphoma kinase (ALK) mutation-positive non-small cell lung cancer (NSCLC); ROS1-positive non-small cell lung cancer; EGFR mutant non-small cell lung cancer; lung adenocarcinoma; lung cancer resistant to EGFR-, ROS1-, or ALK-targeted therapies; lymphoma resistant to ALK-targeted therapies; or the following tumor, cancer or disease dependent on a protein selected from ALK, ROS1 or EGFR, or any mutein thereof: lung cancer, lymphoma, inflammatory myofibroblastoma, colorectal cancer, cerebral glioma, astroblastoma, ovarian cancer, leukemia, breast cancer, thyroid cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, esophageal squamous cell carcinoma, renal cell carcinoma, bronchial carcinoma, prostate cancer, breast cancer, thyroid cancer, pancreatic cancer, neuroblastoma, extramedullary plasmacytoma, plasmacytoma, gastric cancer, gastrointestinal stromal tumor, esophageal cancer, large intestine adenocarcinoma, esophageal squamous cell carcinoma, liver cancer, renal cell carcinoma, bladder cancer, endometrial cancer, melanoma, brain cancer, oral cancer, or sarcoma. 
 
     
     
         36 - 39 . (canceled) 
     
     
         40 . The compound of formula (I), or the pharmaceutically acceptable salt, the enantiomer, the diastereomer, the racemate, the solvate, the hydrate, the polymorph, the prodrug or the isotopic variant thereof, and the mixture thereof according to  claim 1 , wherein, the compound of formula (I) is any one of the following compounds:
 (1) a stereoisomer of   
       
         
           
           
               
               
           
         
          optionally, when the stereoisomer is obtained by the following resolution conditions, its hydrochloride has a retention time of 3.224 min or 5.300 min: chiral normal-phase chromatography (system: SHIMADZU LC-20AP; column: Chiralpak IC-column (250×50 mm, 10 μm particle size); mobile phase: A for Hexane (0.1% IPAm) and B for IPA+ACN (0.1% IPAm); gradient: B %=70% isocratic; flow rate: 100 mL/min; column temperature: room temperature; wavelength: 220 and 254 nm) and prep-HPLC (system: SHIMADZU LC-20AP; column: Luna C18 (250×70 mm, 10 μm particle size); mobile phase: A for 0.05% HCl in H 2 O and B for acetonitrile; gradient: phase B from 0% to 30% in 30 min; flow rate: 140 mL/min; column temperature: room temperature; wavelength: 220 and 254 nm); 
         (2) a stereoisomer of 
       
       
         
           
           
               
               
           
         
          optionally, when the stereoisomer is obtained by the following resolution conditions, its hydrochloride has a retention time of 5.406 min, 6.466 min, 3.052 min or 4.406 min: 3 SFC separations (mobile phase: 80% EtOH+ACN (0.1% NH 3 ·H 2 O) at supercritical CO 2 , flow rate: 120 g/min, gradient time: 12 min, total time: 120 min, volume per injection: 2.0 mL) & (mobile phase: 80% EtOH+ACN (0.1% NH 3 ·H 2 O) at supercritical CO 2 , flow rate: 120 g/min, gradient time: 20 min, total time: 40 min, volume per injection: 10.0 mL) & (mobile phase: 30% EtOH+ACN (0.1% TEA) at supercritical CO 2 , flow rate: 100 g/min, gradient time: 20 min, total time: 40 min, volume per injection: 10.0 mL) and reverse-phase preparative chromatography (hydrochloric acid system); 
         or, (3) the compound of formula (I) is any one of the following compounds: